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Cells Deploy a Two-Pronged Strategy to Rectify Misfolded Proinsulin Aggregates.
Citation | “Cells Deploy A Two-Pronged Strategy To Rectify Misfolded Proinsulin Aggregates.”. Molecular Cell, pp. 442-456.e4. . |
Center | University of Michigan |
Featured |
Featured
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Author | Corey N Cunningham, Jeffrey M Williams, Jeffrey Knupp, Anoop Arunagiri, Peter Arvan, Billy Tsai |
Keywords | ER-phagy, Aggregates, endoplasmic reticulum, mutant proinsulin, protein quality control, reticulon |
Abstract |
Insulin gene coding sequence mutations are known to cause mutant INS-gene-induced diabetes of youth (MIDY), yet the cellular pathways needed to prevent misfolded proinsulin accumulation remain incompletely understood. Here, we report that Akita mutant proinsulin forms detergent-insoluble aggregates that entrap wild-type (WT) proinsulin in the endoplasmic reticulum (ER), thereby blocking insulin production. Two distinct quality-control mechanisms operate together to combat this insult: the ER luminal chaperone Grp170 prevents proinsulin aggregation, while the ER membrane morphogenic protein reticulon-3 (RTN3) disposes of aggregates via ER-coupled autophagy (ER-phagy). We show that enhanced RTN-dependent clearance of aggregated Akita proinsulin helps to restore ER export of WT proinsulin, which can promote WT insulin production, potentially alleviating MIDY. We also find that RTN3 participates in the clearance of other mutant prohormone aggregates. Together, these results identify a series of substrates of RTN3-mediated ER-phagy, highlighting RTN3 in the disposal of pathogenic prohormone aggregates. |
Year of Publication |
2019
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Journal |
Molecular cell
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Volume |
75
|
Issue |
3
|
Number of Pages |
442-456.e4
|
Date Published |
12/2019
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ISSN Number |
1097-4164
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DOI |
10.1016/j.molcel.2019.05.011
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Alternate Journal |
Mol. Cell
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PMID |
31176671
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PMCID |
PMC6688957
|
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